Background/Purpose:

Tofacitinib (CP-690,550) is a novel oral, selective Janus kinase inhibitor being investigated in Phase 3 (P3) as a targeted immunomodulator for the treatment of RA. Here we show pooled P3 and long-term extension (LTE) infection and mortality data for pts with RA.

Methods:

Data were pooled from five randomized double-blind P3 RA studies. Most studies required stable background DMARDs to which tofacitinib was added (NCT IDs: 00960440, 00847613, 00856544, 00853385); one study evaluated tofacitinib monotherapy (NCT ID: 00814307). Pts from these studies had the option to join pts from P2 studies in one of two open-label, LTE studies (NCT IDs: 00413699, 00661661). LTE pts were treated with tofacitinib 5 or 10 mg twice daily (BID) and generally continued their background DMARD therapy as appropriate.

Deaths in the P3 programs and those that occurred after February 25, 2009 in the LTE studies were classified by an independent, blinded Cardiovascular Safety Endpoint Adjudication Committee (CV-SEAC).

Results:

A total of 3030 pts with RA from P3 and 3227 from LTE studies were included in the analyses, resulting in approximately 2000 and 3000 pt-years (pt-y) of exposure to tofacitinib, respectively (Table). In the P3 studies, there were a total of 12 CV-SEAC-classified all-causality deaths (5 due to infections, 3 other [noncardiac], 2 cardiac, 1 trauma and 1 cause unknown) and 2 deaths with adjudication not available. In the LTE studies, there were a total of 8 CV-SEAC-classified all-causality deaths (3 due to infection, 2 other [noncardiac], 1 cancer, 1 cardiac, and 1 cause unknown) and 12 deaths were not adjudicated.

Concerning infections, the most common treatment-emergent infection adverse events (AEs) (>5% in any treatment group) in LTE studies were nasopharyngitis, upper respiratory tract infection, urinary tract infection, bronchitis, herpes zoster, and influenza. Infection AEs in P3 studies were all <5% in any treatment group. Most infection AEs were mild or moderate and discontinuation due to infection was infrequent (approximately 12%). There was no apparent increase in the rate of non-serious or serious infections over time. The rates of infection events were similar regardless of whether pts received tofacitinib as monotherapy or with background DMARDs. Although the rate of serious infections among tofacitinib 10 and 5 mg BID groups was similar in P3, in the LTE studies that rate for 10 mg BID was approximately twice that of 5 mg BID (4.9 vs 2.3 /100 pt-y). Events of opportunistic infections, including tuberculosis, were uncommon.

Conclusion:

In P3 and LTE studies, mortality rates were consistent with the expected rate in pts with active RA, including those receiving therapy with other DMARDs. The safety profile of tofacitinib with regard to infection AEs was consistent with the previously reported P2 experience and no new safety signals were observed.